Type-1 diabetes is caused by the autoimmune destruction of insulin producing β-cells in the pancreas. β-cell apoptosis involves a set of signaling cascades initiated by interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). (Chou et al., ACS Chem. Biol. 2010 Aug. 20; 5(8):729-34). IL-1 β and TNF-α induce NFκB expression, and downstream activation of gene expression is thought to occur through nitric oxide (NO) signaling, which both increases endoplasmic reticulum stress-response pathways and decreases β cell-specific functions. NO is a highly reactive molecule that inhibits the electron-transport chain, leading to decreases in glucose oxidation rates, ATP generation, and insulin production; cellular nitrite is more stable and serves as a surrogate marker for NO. NFκB activation and IFN-α-induced STAT-1 signaling work together to effect β-cell apoptosis, mainly involving the intrinsic apoptotic pathway in both rodents and humans. The downstream effector of this cascade, caspase-3, results in apoptosis and the loss of the ability to secrete insulin in response to glucose stimulation. Cnop et al., Diabetes 54, (Suppl 2), S97-107, 2005; Formoni et al., Diabetologia 51, 298-308, 2008; Soldevila et al., J. Autoimmun. 4, 291-306, 1991; Darville et al., Diabetologia 41, 1101-1108, 1998. Kharroubi et al., Endocrinology 145, 5087-5096, 2004; Mandrup-Poulsen et al., Diabetologia 39, 1005-1029, 1996.
For decades, the standard of care for this disease has been insulin therapy via intramuscular injection. Current approaches to develop new treatments have prioritized islet transplantation) and directed stem-cell differentiation, while many technological advances have focused on glucose detection and insulin delivery. Recent development of techniques to treat diabetic mice with partially differentiated stem cells indicates that procedures resulting in an increase in beta-cell mass can ameliorate type-1 diabetes. While cell-based treatments show promise, a chemical intervention capable of restoring glycemic control in type-1 diabetes would have enormous impact clinically, by enabling an in vivo pancreatic effect while avoiding the need for immunosuppression.